2-amino-2-benzylthio-methyl-1,3-alkanedials

ABSTRACT

Azadioxabicyclooctane compounds are prepared by the reaction of tris(hydroxyhydrocarbyl)methylamine with an aldehyde. These compounds can then be halogenated to the corresponding halogensubstituted acid salt followed by hydrolysis to form 2-amino-2halohydrocarbyl-1,3-propanediols. The diols can then be reacted with a hydrosulfide salt to form a 2-amino-2-mercaptohydrocarbyl1,3-propanediol which is a known anti-radiation compound. The diols can also be reacted with benzyl mercaptide to form the 2amino-2-benzylthiohydrocarbyl-1,3-propanediol which under debenzylation conditions also forms the 2-amino-2mercaptohydrocarbyl-1,3-propanediol.

Unite States Patent [191 Cobb Z-AMINO-Z-BENZYLTHIO-METHYL-1,3-ALKANEDIALS Inventor: Raymond L. Cobb, Bartlesville,

Okla.

Assignee: Phillips Petroleum Company, Bartlesville, Okla.

Filed: Jan. 3, 1972 Appl. No.: 215,193

Related US. Application Data Division of Ser. No. 472,733, July I6,1965, Pat. No. 3,660,488.

US. CL... 260/5705 S, 260/307 R, 260/453 R,

260/563 R, 260/570.6, 260/584 R, 260/999 Int. Cl. C07c 87/28 Field ofSearch 260/5705 S References Cited I UNITED STATES PATENTS 8/1929 Hahlet al. 260/5705 X 3.50l,769 3/1970 Crowther et al 260/50l.l7

Primary Examiner-Robert V. Hines 5 7 ABSTRACT Azadioxabicyclooctanecompounds are prepared by the reaction oftris(hydroxyhydro'carbyl)methylamine with an aldehyde. These compoundscan then behalogenated to the corresponding halogen-substituted acidsalt followed by hydrolysis to form 2-amino-2-halohydrocarbyl-l,S-propanediols. The diols can then be reacted with ahydrosulfide salt to form a 2-amino-2-mercaptohydrocarbyl-1,3-propanediol which is a known anti-radiationcompound. The diols can also be reacted'with benzyl mercaptide to formthe 2-amino- 2benzylthiohydrocarbyl-1,3-propanediol which underdebenzylation conditions also forms the 2-amino-2- mercaptohydrocarbyll,3-propanediol.

2 Claims, No Drawings l 2-AMlNO-2-BENZYLTHIO-METHYL-l ,3-

- ALKANEDIALS This application is a divisional of my copendingapplication Ser. No. 472,733, filed July 16, 1965, now US. Pat. No.3,660,488.

This invention relates to novel compounds. in one aspect this inventionrelates to derivatives of alkanediols having multifunctional chemicalgroups substituted thereon. in another aspect, thisinvention relates tonovel 2-amino-2-halomethyl-l ,3-propanediols and their salts. In yetanother aspect this invention relates to a method for preparing thesenovel compounds.

The object of this invention is to provide a multifunctional chemicalderivative of an alkanediol which is a useful intermediate in thepreparation of anti-radiation drugs. Another object of this invention isto provide an alkanediol having an amino and halomethyl functional groupin the molecule. A further object of the invention is to provideprocesses for synthesizing these types of compounds. Other objects andadvantages will be apparent from the following description of theinvention, and the novel features will be particularly pointed outhereinafter in connection with the appended claims.

The novel compounds of the present invention are prepared by a processillustrated by the following equation:

R n-tb-ort H0-R- -NH:+2R"-CH 3- OH I I II l hydrolysis In the aboveformulae, R is selected from the group consisting of hydrogen and alkylradicals containing from one to three carbonatoms, R" is selected fromthe oup s n p l syl n v rt s a ysl k ene radicals containing from I to.20 carbon atoms, R" is selected from the group consisting of alkyl,aryl, alkaryl, and aralkyl radicals including those having up to 10carbon atoms, X is selected from the group consisting of chlorine andbromine.

ln carrying out the preparation of these novel compounds, at least 2mols of the aldehyde (Formula ll) are contacted with each mol of thetris( hydroxyhydrocarbyl)methylamine compound (Formula I) underconditions such that the reaction takes place with the formation ofabout 2 mols of water per mol of the aforementioned methylamine. Thisreaction is carried out at elevated temperatures in the presence of asuitable inert aliphatic or aromatic solvent such as benzene, toluene,pentane, heptane and the like. The water is removed as it is formed. Asuitable apparatus for azeotropically removing the water from thereaction mixture is described in US. Pat. No. 2,994,644, Clay, issuedAug. l, 1961. The reaction product consisting of the bicyclo compounds(Formula'lll) 'is halogenated by contact under reaction conditions witha halogenating agent selected from the group consisting of SOCl SOBr PClPCI PBr and a mixture of Br or C1 with R" P, wherein R is a saturatedacyclic, saturated cyclic, or aromatic radical having up to 20 carbonatoms, e,g'., tributylphosphine, triphenylphosphine, etc., wherein thehalogenated compound represented by .Formula ,IV is produced. Thiscompound is then hydrolyzed by contact with water under reactionconditions to provide the novelcompounds of my invention (Formula.

Some examples of the invention compounds produced by this process are:

2-amino-2-chloromethyll ,3-propanediol Z-amino-Z-bromomethyl-l,3-propanediol 2-amino-2-( 8-chloro-n-decyl l ,3-propanediol 2-amino-2-(2-bromoethyl l ,3-propanediol5-amino-5-(20-chloro-n-eicosyl)-4,6-nonanediol 2-amino-2-(p-chlorobenzyll ,3-propanediol 2.-amino-2-(3-bromocyclopentyl)-1,3-propanediol2-amino-2-(2-chlorophenyl )-l ,3-propanediol4-amino-4-(bromomethyl)-3,5-hexanediol 4-amino-4-(6-chloro-2,3-dimethylhexyl)-3,5-

heptanediol 5-amino-5-.(20-chloro-n-eicosyl)-4,6-di-n-propyl-4,6-nonanediol 2-Amino-2-chloromethyll ,3-propanediol, one of thecompounds in the class of novel compounds produced by this method hasutility as a chemical intermediate useful for the preparation ofZ-amino-Z-mercaptomethyl-l,3-propanediol which is useful as ananti-radiation drug. The reaction is represented as follows:

This drug can also be prepared by treating 2-amino-2-chloromethyl-l,3-propanediol with sodium benzyl mercaptide to formZ-amino-Z-berizylthiomethyl-l ,3-

. propanediol which is then debenzylated with sodium in liquid ammoniaora similar reagent. These reactions can be illustrated by the followingequations:

reagents pound can -be converted to the corresponding bunte 7 salt.The'bunte salts are salts of the S-esters of thiosulfuric acid and areprepared by contacting the subject compound with sodium or thalliumthiosulfate. The bunte compound is prepared either in the metallic saltform or in the free acid form as exemplified by the following compound:S-[2-amino-2,2- bis(hydroxymethyl)ethyl]thiosulfuric acid.

It is to be understood that the invention is not to be limitedspecifically to the 2-amino-2-halomethyl-l,3- propanediol but is toinclude the entire class of compounds shown in generic Formula V as wellas their simple derivatives such as those shown above and their acidsalts. These novel compounds all are valuable as alkylating agents orintermediates'for the production insecticides, repellents, and otheragricultural chemicals.

his to be understoodthat thesecompounds can be prepared in a continuousmedium in the solvents disclosed hereinabove and can be recovered byconventional methods, such as crystallization, distillation, solventextraction, and the like. These recovery operations are conventionalsteps and are familiar to those skilledin the art. The technique for therecovery of specific compounds can vary somewhat due to differences inmolecular weight, solubility, boiling point and the like.

The invention can be further illustrated by the following examples.

' EXAMPLE I 2 Preparation of l-aza-5-hydroxymethyl-2,S-diphenyl-3,7-dioxabicyclo(3,3,0)octane A 242 gram quantity (2 mols) oftris(hydroxymethyl)methylamine and 424 grams (4 mols) of benzaldehydewere charged into a stirred reactor together with l liter of xylene. Themixture was stirred and refluxed for about 7.5 hours during which timethe theoretical amount of water (about 4 mols) was collected in a DeanStark trap. Most of the xylene was removed leaving a residual oil. Thisoil was dissolved in ether and the solution cooled until crystalsformed. A total of 377 grams of white crystals which melted at about93-95C. was obtained. This melting point agreed with the literaturemelting point for l-aza-5-hydroxymethyl-2,8-diphenyl-3,7-dioxabicyclo(3,3,0)octane. Preparation of pr p qdishydre qride 2-amino-2-chloromethyll ,3- I

A 99 gram (0.33 mol) quantity of the bicyclo compound prepared above wascharged into a stirred vessel together with 350 ml of benzene. A 44 gram(0.37 mol) quantity of thionyl chloride SOCI was added to this mixturedropwise at room temperature and the mixture was stirred for anadditional hour at room temperature. The contents of the vessel werethen heated slowly to reflux and maintained at reflux for 1 hour duringwhich time a white crystalline solid was formed. A 60 ml quantity of l2Nhydrochloric acid in ml of water was then added to the mixture which wasthen stirred vigorously with heating. The formation of benzalde hyde wasobserved. The benzene was allowed to evaporate and the reaction mixturewas stirred vigorously on the steam bath 3 hours after which it wasextracted with diethyl ether to remove any remaining benzaldehyde. Theremaining aqueous solution was evaporated to dryness. The residue wascrystallized from isop'ropanol, containing enough water for solutionwhen hot, yielding a total of 44 grams of white crystals 76 per cent oftheoretical). The portion of the recrystallized product melting at92-94C. was subjected to elemental analysis with the following results:

Element Calculated for C,H,,Cl- NO Found C 27.29 26.7 H 6.30 6.7 N 7.967.3

Thus, the analysis of the product agrees with the formula for2-amino-2-chloromethyl-l,3-propanediol by drochloride.

A run was carried out to make the 2-amino-2- chloromethyl-l,3-propanediol hydrochloride without steam bath temperature. An oilformed, followed by Element Calculated for c,..H,,.c|No,-Hc| Found C61.37 59.0 H 5144 5.6 N 3.98 3.8

' In addition, a quantity of the partially hydrolyzed product,4-chloromethyl- 4-hydroxymethyl-2-phenyloxazolidine hydrochloride wasisolated from hot acetonitrile as a white crystalline product having amelting point of l82l 84C. The elem ntele elysie s as fo w After coolingthe slurry of crystals to room temperature, 175 ml of concentratedhydrochloric acid and 500 ml water were added. The mixture was stirredvigorously at 90-95C. for 4 hours, causing rapid decomposition of thesolid. The phases were separated while hot,

and the organic layer was washed once with 150 ml of concentratedhydrochloric acid. The latter was combined with the aqueous layer whichwas then washed with benzene, the benzene washings being discarded. Thewashed aqueous solution was saturated with hydrogen chloride at C.Cooling in an ice bath gave 354. grams of the2-amino-2-chloromethyl-1,3- propanediol hydrochlorideas a whitecrystalline solid after washing well with isopropyl alcohol,tetrahydrofuran, and ether. Its melting point was 94-96C. Concentrationof the mother liquor to about 200 ml and dilution of the solution with500 ml each of isopropyl alcohol and tetrahydrofuran gave another 64grams of product for a'total yield of 79 percent of theoretical.

The elemental analysis for this product was as follows:

Calculated for C,H,,,ClNO,-l-1Cl In addition, both infrared and NMRanalyses of the product were consistent with the postulated structure ofthe product.

EXAMPLE u A Preparation of 2-amino-2-benzylthiomethyl l,3- propanediol,To a solution of 550 grams 13.7 mols) of sodium hydroxide and 750 grams(6 mols) of benzyl mercaptan in 500 ml each of methanol and oxygen-freewater was added under nitrogen with stirring a suspension of 1,170 grams(6.6 mols) of 2-amino-2-chloromethyl- 1,3-propanediol hydrochloride,such as that prepared in Example 1, in 1,500 ml water. The resultingmixture product oil, in the form of the free base, .was removed, and theaqueous solution was extracted twice with 1 liter portions of chloroform(the product oil was insoluble in hydrocarbons and diethyl ether). Theextracts were combined with the product oil and the resulting solutionwas washed twice with water. After drying over magnesium sulfate, theoil was filtered. The solvents were stripped from the oil and it wasthen heated 6 at C. and at 0.5 mm pressure for 20 hours to give 906grams (66 per cent oftheory) of the desired product. The elementalanalysis for thisproduct was as follows:

Calculated for C Hl NO S Element Found C 58.12 57.7 H 7.54 8.1 N. 6.165.8 S 14.11 14.5

The free base product slowly crystallized on long standing giving hardwhite crystals, recrystallized from diethyl ether containing a littletetrahyclrofuran, which melted at 6l-63C. Elemental analysis found wasas follows:

Found The product prepared from the same reactants,in another run, wasisolated as the. hydrochloride of 2-amino-2-benzylthiomethyl-1,3-propanediol. After acidification of theinitial reaction mixture, the unreacted benzyl mercaptan was removed bybenzene extraction and the aqueous solution of the product in thehydrochloride form was adjusted to about 4 N in hydrochloricacid.Crystallization from this liquid and recrystallization fromtetrahydrofuran 1 gave a 73 per cent yield of crystals with a meltingpoint of l08-l 10C.

EXAMPLE Ill Preparation of 2-amino-2-bromomethyl-l ,3- propanediolhydrobromide In a manner similar to that of Example 1, 121 grams (1 mol)of tris(hydroxymethylIlmethylamine, 212

grams (2 mols) of benzaldehyde, and 600 ml xylene were refluxed with theremoval of water to produce a xylene solution of the bicyclo compound.The xylene solution was cooled and was mixed with 202 grams (1 mol) oftributylphosphine. To this solution was added 160 grams (1 mol) ofelemental bromine at 30-40C. After addition of the bromine. wascomplete, the mixture was heated at C. for 1 /2 hours then 200 mlconcentrated hydrobromic acid and 300 m1 of water were added. Themixture was stirred under reflux for 3 hours, cooled to roomtemperature, and the aqueous phase was removed and evaporated underreduced pressure. A total of 129 grams of crystalline product wasrecovered from this residue by crystallization from various solvents. A47 gram portion of 2-amino-2- bromomethyl-l ,3-propanediol in thecrystalline hydrobromide monohydrate form which melted at about 89-90C.and had an elemental analysis as follows:

Element Calculated for C H,,,BrNO,'Hl3r'H,O Found c 16.98 17.2 H 4.634.7 N 4.95 4.8

v 7 Thus, the analysis agreed with the formula for 2-amino-2-bromomethyl-1,3-propanediol hydrobromide monohydrate.

EXAMPLE IV Reaction of 2-amino-2-bromomethyl-l,3-propanediol andThallium Thiosulfate (Bunte Salt Reaction) A 28.4 gram (0.1 mol)quantity of the compound prepared above was contacted with 52.] grams(0.1 mol) of thallium thiosulfate in the presence of 200 ml water at50C. for 1 week. The mixture was then cooled, the thallium salts werefiltered out, and the water was evaporated on a steam bath leaving theprodriot in the form of a viscous oil. A 19.5 gram quantity (90 per centof theoretical) of the bunte salt (acid form),S-[2-amino-2,2-bis(hydroxymethyl) ethyl1thiosulfuric acid was obtainedby crystallization from methanol and tetrahydrofuran. The elementalanalysis for the product was as follows:

Obviously many modifications and variations of the present invention arepossible in the light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims the inventionmay be practiced otherwise than as specifically described herein.

What I claim is:

1. As a composition of matter, a l,3-propanediol compound of the formulawherein R is selected from the group consisting of hydrogen and an alkylradical containing l-3 carbon atoms.

2. A composition according to claim 1 which is 2-amino-Z-benzylthiomethyll ,3-propanediol.

1. AS A COMPOSITION OF MATTER, A 1,3-PROPANEDIOL COMPOUND OF THE FORMULA2. A composition according to claim 1 which is2-amino-2-benzylthiomethyl-1,3-propanediol.